Parameter | Midostaurin | CGP52421 | CGP62221 | |||
---|---|---|---|---|---|---|
Value | Reference | Value | Reference | Value | Reference | |
mol. wt. (g/mol) | 570.6 | 586.6 | 556.6 | |||
logPo:w | 5.49 | Internal database | 4.76 | Internal database | 4.68 | Internal database |
pKa | 11.2 | Predicteda | 10.8 | Predicteda | 11.2 | Predicteda |
Compound type | Monoprotic base | |||||
fup | 0.00015 | Internally measured | 0.00021 | Internally measured | 0.00038 | Internally measured |
B/P | 0.55 | 0.55 | Assumed same as parent | 0.55 | Assumed same as parent | |
Plasma-binding component | AGP | AGP | AGP | |||
First-order absorption | ||||||
Fa | 0.85 (0.65, advSM) | User defined (optimized) | ||||
ka (h−1) | 1.5 (0.683, advSM) | |||||
Lag time (h) | 0.3 | |||||
Qgut (l/h) | 5.23 | Simcyp predicted | ||||
fugut | 0.3 | |||||
Peff, man (10−4 cm/s) | 0.835 | |||||
Caco-2 (10−6 cm/s) | 1.4 | Internally measured | ||||
Caco-2 reference (10−6 cm/s) | 17 | |||||
Minimal with single adjusting compartmental distribution | ||||||
Q (l/h) | 3 (2.889, AML/advSM) | Estimated from clinical PK data (a single-dose trial) | 10 | Estimated from clinical PK data (a single-dose trial) | 2 | Estimated from clinical PK data (a single-dose trial) |
Volume (Vsac [l/h]) | 0.82 (0.623, AML/advSM) | 1.8 | 1.1 | |||
Vss (l/h) | 1 (0.742, AML/advSM) | 1.3 | 1.3 | |||
Elimination | ||||||
Hepatic CL by CYP3A4 (%) | 100 | Estimated from human ADME study | 90 | Estimated from human ADME study | 90 | Estimated from human ADME study |
CLint, CYP3A4 formation of CGP52421 (µl/min per picomole CYP3A4) | 9.3 (3.9, AML/advSM) | See Elimination | ||||
CLint, CYP3A4 formation of CGP62221 (µl/min per picomole CYP3A4) | 9.3 (3.9, AML/advSM) | |||||
CLint, CYP3A4 formation of other metabolites (µl/min per picomole CYP3A4) | 6.6 (2.8, AML/advSM) | 3.18 (0.557, AML patients) | 1.19 | |||
Additional HLM CL (µl/min per milligram protein) | 48.4 (6.48, AML patients) | 18.1 | ||||
Active uptake into hepatocytes | 1 | Default | ||||
CLR | 0 | See Elimination | ||||
CYP3A4-related interaction | ||||||
Reversible inhibition CYP3A4 Kiu (µM) | 0.25 | Internally measured (Supplemental Table 2) | 0.44 | Internally measured (Supplemental Table 2) | 0.25 | Internally measured (Supplemental Table 2) |
TDI KI, total (μM) kinact (1/h) | 1.02 2.8 | Internally measured (Supplemental Table 3) | 1.97 3.0 | Internally measured (Supplemental Table 3) | 2.01 4.62 | Internally measured (Supplemental Table 3) |
Induction of CYP3A4 Indmax (fold) IndC50 (µM) | 9.14 0.0026 | Internally measured (Supplemental Table 4) and optimized | 10.8 0.0053 | Internally measured (Supplemental Table 4) and optimized | 11.97 0.0027 | Internally measured (Supplemental Table 4) and optimized |
B/P, blood-to-plasma ratio; CLR, renal CL; fup, fraction of unbound drug in plasma; Ind50, half-maximum induction rate; IndC50, concentration of inducer at half-maximal induction; Indmax, maximal fold induction over vehicle control; ka, absorption rate constant; KI, concentration producing a half-maximal rate of activity reduction; kinact, maximal rate of activity reduction; Kiu, unbound inhibition constant; logPo:w, water partition coefficient; Peff, man, effective permeability in man; Qgut, nominal flow through the gut.
↵a Determined using ADMET Predictor version 6.5 (Simulations Plus).